Presence Of Pro-inflammatory Mediators Research Articles

128. Selective presence of proinflammatory mediators in the hippocampus of HIV-1 transgenic rats

128. Selective presence of proinflammatory mediators in the hippocampus of HIV-1 transgenic rats

Leptin, adiponectin, interleukin-6 and tumor necrosis factor-α in obese adolescents

Purpose : Obesity is associated with insulin resistance. Insulin resistance and the presence of pro-inflammatory mediators are thought to cause a state of vascular endothelial dysfunction, an abnormal lipid profile, hypertension, and vascular inflammation. These chronic inflammatory responses, which are characterized by abnormal cytokine production, lead to activation of a pro-inflammatory signaling pathway. Leptin is an important mediator of inflammatory processes and immune-mediated diseases. The purpose of this study was to investigate the relationship between leptin and various cytokines associated with obesity in adolescents. Methods : Sixty-six obese adolescents (between 16-17 years of age, obesity index >130%) and 26 normal controls were included in this study. Obesity index and body mass index (BMI) were calculated. Serum lipid profile, AST and ALT were tested after 10 hours of fasting. Tumor necrosis factor alpha (TNF-α) and Interleukin-6 (IL-6) levels were measured by ELISA. Insulin, adiponectin, and leptin levels were estimated by radioimmunoassay. Results : Leptin was significantly higher in the obese adolescents compared to the control adolescents (12.0±6.8 ng/mL vs 6.3±1.0 ng/mL). TNF-α, IL-6, and insulin were significantly higher in the obese adolescents. Adiponectin was significantly lower in the obese group than the control group (3.3±1.9 µg/mL vs 5.0±1.4 µg/mL). Leptin had positive correlations with obesity index, BMI, and IL-6. Conclusion : In obese adolescents, leptin, TNF-α, IL-6, and insulin might be important mediators of obesity. Further clinical research is necessary to ascertain leptin as a predictor of cardiovascular diseases and to develop a guideline for clinical intervention.

Analysis of the expression of HLA class I, proinflammatory cytokines and chemokines in primary tumors from patients with localized and metastatic renal cell carcinoma

Changes in the human leukocyte antigen (HLA) class I expression and cytokine and chemokine production both by cancer cells and by normal surrounding tissue are believed to be responsible for immune escape and tumor progression. In this study, we compared the tumor expression levels of HLA heavy chain (HLAhc), beta-2-microglobulin (beta2m), chemokines (Interferon-gamma-inducible Protein-10 (IP-10), Interferon-inducible T-cell Alpha-Chemoattractant (I-TAC), Stromal cell-Derived Factor-1 (SDF-1), Macrophage Inflammatory Protein-1-alpha (MIP-1-alpha) and Regulated upon Activation, Normally T-Expressed, and presumably Secreted (RANTES)) and cytokines (Vascular Endothelial Growth Factor (VEGF), Interferon-gamma (IFN-gamma), Interleukin-10 (IL-10), Tumor Growth Factor-beta (TGB-beta)) in primary tumors and adjacent normal tissues from patients with localized and metastatic renal cell carcinoma (RCC) using a quantitative real-time polymerase chain reaction technique. We report that the expression of HLAhc, beta2m and the studied cytokines and chemokines (except for SDF-1) was significantly higher in the tumor (29 samples) than in the normal tissue (14 samples). When we compared the tumor expression levels between patients with localized RCC and patients with advanced metastatic stage, we found that the messenger RNA expression levels of HLAhc and beta2m were much lower in patients with metastatic RCC (6 cases) than in patients with localized cancer (23 cases), with levels similar to those in normal tissue. This was also confirmed on a protein level by immunohistological labeling of tumor tissues. Thirty-nine percent of the analyzed RCC tumors showed partial loss of HLA class I molecules, while 6% of the tumors showed HLA class I total loss. The expression of IP-10, SDF-1 and VEGF-c was also significantly lower in patients with advanced tumor, while the IFN-gamma expression in metastatic RCC was not detectable. Our findings show that primary RCC tumors are characterized by a high expression of HLAhc and a presence of proinflammatory mediators and chemokines. We also observed that disease progression and development of metastasis in RCC are associated with decreased expression of HLAhc, beta2m, IP-10, SDF-1 and IFN-gamma. This microenvironment may suppress the cytotoxic response, creating conditions that favor tumor escape and cancer progression.

Photodynamic therapy and anti‐tumor immunity

Photodynamic therapy (PDT) efficacy appears to be enhanced in the presence of an intact immune system and PDT has been shown to augment anti-tumor immunity. The mechanisms leading to the enhancement of the host immune response to tumor are unclear. Anti-tumor immunity depends upon the presence of activated antigen presenting cells (APCs). These cells are activated by their recognition of components released by pathogens, viruses, dead cells, and the presence of pro-inflammatory mediators. Activated APCs stimulate the generation of cytokine secreting effector cells. Therefore, we have hypothesized that PDT generated inflammatory mediators and components released from tumor cells killed by PDT results in the activation of APCs capable of stimulating effector T-cell proliferation and cytokine secretion. To determine the effect of PDT on APCs, tumor draining lymph nodes (TDLNs) of EMT6 or Colo 26 tumor bearing mice were isolated 24 hours after Photofrin-PDT and flow cytometry was used to detect the presence of APCs secreting the T cells stimulatory cytokine, IL-12. APCs were also isolated from TDLNs and used to stimulate T-cell proliferation and secretion of interferon-gamma (IFN-gamma). PDT results in an increase in IL-12 expressing APCs in the TDLN. This increase was accompanied by an increase in the ability of APCs isolated from TDLNs of PDT-treated mice to stimulate T-cell proliferation and T-cell secretion of IFN-gamma. Our results indicate that APCs isolated from PDT-treated mice exhibit an enhanced ability to stimulate T-cell proliferation and IFN-gamma secretion, suggesting that PDT results in increased APC activity.

Ascorbid Acid Supplementation Reduces Severity of Exercise-Induced Asthma

PURPOSE: Ascorbic acid (vitamin C) is a major antioxidant in the airways. Data on the effect of antioxidants on exercise-induced asthma (EIA) is equivocal. Therefore, the aim of this study was to determine the effects of ascorbic acid (vitamin C) supplementation on the severity of EIA. METHODS: Eight subjects with EIA participated in a randomized, placebo controlled double-blind cross-over trial. Subjects entered the study on their normal diet and were then placed on either 2 weeks of ascorbic acid supplementation (1500mg/day) or placebo, followed by a 1 week washout period, before crossing over to the alternative diet. Pre- and post-exercise pulmonary function was assessed at the conclusion of each treatment period. In addition, urine samples were collected pre- and post-exercise and assayed for the presence of pro inflammatory mediators, cysteinyl leukotrienes (LT) C4-E4 and 9α, 11β- prostaglandin (PG) F2 which have been implicated in the pathogenesis of EIA. Urine was assayed for hydrogen peroxide (H2O2), as a marker of oxidative stress. Diet was monitored through 24-hour dietary recall to ensure that diet was not significantly different between the trials. Pre- and post exhaled breath nitric oxide (FENO) was measured as a noninvasive indicator of airway inflammation. RESULTS: Ascorbic acid supplementation significantly reduced (p <0.05) the mean maximum fall in post-exercise FEV1 (−6.4 ± 2.4%) compared to normal diet (−14.3 ± 1.6%) and placebo (−12.9 ± 2.4%). Post-exercise FENO was reduced on ascorbic acid supplementation (23.8 ± 7.7 ppb) as compared to normal diet (48.4 ±16.3 ppb) and placebo (34.1 ± 7.8 ppb). Ascorbic acid supplementation induced significant reductions (p <0.05) in urinary LTC4-E4 on the ascorbic acid supplementation (5.3 ±1.7 ng/mmol of creatinine) compared to the normal diet (15.0 ±4.0 ng/mmol/creatinine) and placebo (11.1 ±3.1 ng/mmol/creatinine). Similarly, urinary 9α, 11β-PGF was significantly reduced on the ascorbic acid supplementation (8.5 ±1.7 ng/mmol/creatinine) compared to the normal diet (20.0 ±4.5 ng/mmol/creatinine) and placebo (13.0 ± 1.8 ng/mmol). Furthermore, significant reductions (p <0.05) in urinary HO were observed on the ascorbic acid supplementation (5.6 ± 1.3 mmol/L) compared to placebo (23.6 ±5.1 mmol/L) and normal diet (12.6 ±2.9 mmol/L). CONCLUSION: These data indicate that high dose ascorbic acid supplementation reduces the severity of EIA. This reduction in the severity of EIA may occur through a mechanism by which ascorbic acid reduces reactive oxygen species, thereby leading to a reduction in bronchoconstrictive mediators.

Montelukast in the treatment of asthma as a systemic disease

Asthma affects 300 million people worldwide. The common association of asthma with allergic rhinitis and the presence of proinflammatory mediators in the circulation of patients provide strong evidence for the need to treat asthma as a systemic disease. The leukotriene receptor antagonist montelukast is a disease-specific oral medication that has dual effects on airway smooth muscle cells and inflammatory processes. This review describes recent randomized, controlled studies of montelukast in asthma and allergic rhinitis in adults and children as young as 3 months old. Montelukast treatment consistently produced significant reductions in asthma exacerbations. While many patients may benefit from montelukast as monotheray, combination treatment for chronic asthma with inhaled corticosteroids is advocated as being rational. Significant improvements in symptoms and quality of life were observed in allergic rhinitis patients. Montelukast is well tolerated in patients of all ages. Long-term studies are underway to determine its effects on airway remodeling.